Population-based surveys report methamphetamine (meth) use rates 20 times higher among men who have sex with men (MSM) compared with the general population. Meth use is also a driving force in the MSM HIV epidemic: meth use has been consistently associated with high-risk sexual behavior and sexually transmitted diseases. Despite these alarming data, relatively few interventions have been tested among meth-using MSM, and no studies have tested the efficacy of pharmacologic interventions in reducing meth use in this population. A recent pilot study using mirtazapine, an FDA-approved drug with dual dopaminergic and serotonergic properties, significantly reduced meth withdrawal symptoms when compared to placebo. We propose to expand upon these promising results by conducting a study of intermediate size (60 participants) and length (3 months of follow-up) to assess efficacy of mirtazapine in reducing meth use among high-risk MSM. The specific aims of our study are: 1) To test the hypothesis that mirtazapine 30 mg daily will reduce meth use significantly more than placebo among meth-dependent MSM, as determined by the proportion of meth-negative urines and by self- report of meth use in the mirtazapine versus placebo group. 2) To measure the acceptability of mirtazapine and placebo among meth-dependent MSM, by determining (via electronic pill caps and self-report) medication adherence to mirtazapine and placebo. 3) To measure the safety and tolerability of mirtazapine and placebo among meth-dependent MSM, as determined by the number of adverse clinical events in the mirtazapine and placebo arms. We will enroll sexually active, meth-dependent MSM who will be randomized 1:1 to receive mirtazapine or placebo for 90 days. We include both urine testing and behavioral risk assessments. Participants will be seen weekly for urine drug testing and for brief substance use counseling. Behavior will be assessed using standardized measures via audio computer-assisted self-interview (ACASI). If promising, study results will be used to design a phase III clinical trial to determine if mirtazapine's effects on reducing meth use lead to reductions in meth-associated sexual risk. [unreadable] [unreadable] [unreadable] [unreadable]